The present invention relates to devices and methods for sensing multiple analytes in fluids, and more specifically to devices and methods for determining the concentration of multiple analytes simultaneously in an unknown fluid sample using optical interrogation.
Analytical chemistry has been instrumental in providing healthier and more comfortable living for billions around the world. For example, to protect the environment, samples of water, air, microorganisms, tissues from plants and animals are analyzed. In the medical field, samples of body tissues and physiological fluids are analyzed on a routine basis to provide information on patients, for diagnosis as well as for monitoring purposes. In the past, analyses were mostly done by collecting samples and bringing them to a laboratory for analysis by large, expensive pieces of equipment. In other cases, analyses were even done manually using wet chemistry. To determine the concentration or presence of different analytes in an unknown sample, often the unknown sample, such as a liquid, has to be divided into many portions and analyzed one analyte at a time. Thus, the analysis of multiple analytes in an unknown sample is cumbersome and time-consuming.
Some examples of instruments that can sense multiple analytes simultaneously are AVL Opti CCA, Chiron Centaur, Instrumentation Laboratory GEM 201, I-STAT Portable Analyzer, etc. AVL Opti CCA is a portable analyzer that provides the measurement of pH, total hemoglobin, oxygen saturation, blood gas, and electrolyte parameters. The analyzer uses Opti CCA cassette system, which is a single use cassette system incorporating optical sensing technology. The cassette contains optical fluorescence sensors, one for each of pH, PCO2, PO2, Na+, K+, iCa++ (ionic calcium) and Clxe2x88x92. The analytes SO2 and tHb (total hemoglobin) are measured using optical absorbance and reflectance, respectively. Diameterics IRMA is also a portable analyzer that measures pH, PCO2, PO2, Na+, K+, iCa++, Clxe2x88x92, Hct (hematocrit), and glucose. For Diameterics IRMA, disposable cartridges are configured to provide several combinations of these parameters using one electrochemical sensor for each parameter. The glucose cartridge is a stand alone cartridge that uses optical reflectance technology. The I-STAT device also uses cartridges based on electrochemical sensors, one for each parameter. Several different cartridges are available for different combinations of the parameters that include pH, PCO2, PO2, Na+, K+, iCa++, Clxe2x88x92, Hct, glucose, blood urea nitrogen (BUN), and Creatinine. It is to be noted that although a large number of parameters can be measured using these analyzers, none of the analyzers can be used to analyze all the parameters on one cartridge. Moreover, the analyzers often use a combination of both optical and electrochemical sensing technologies.
Although simultaneous analysis of a plurality of analytes have been done, the analytical instruments are often complex. For example, prior methods in sensing multiple analytes optically involve using multiple optical sensors, each of which is optimized for sensing one specific analyte. The sensors are designed to be specific to the analyte they target and not responsive to any other analyte that might be present in the sample. One disadvantage of such methods is that one has to design a highly specific sensor. Designing for such high specificity is costly, time-consuming, and not always practical. Moreover, the sensors so designed can be used only in well-defined samples, which are known not to contain interfering species of analytes. Failure to ensure such specificity in the sensor could lead to unreliable measurements. For example, some blood glucose sensors cannot be used when acetaminophen is present in the blood sample. Another disadvantage of this design is that each of the sensors requires a different method on interrogation. For example, a pH sensor may be based on optical absorbance of an indicator at one wavelength while an oxygen sensor may be based on fluorescence quenching at another wavelength. A third method, such as colorimetry, may have to be used for glucose sensing, and so on, for other analytes. As a result, the instrument for analyzing multiple components may be complicated, expensive, bulky, and highly power-consuming.
Recently, Wolfbeis et al., xe2x80x9cSet of luminescent decay time based chemical sensors for clinical applicationsxe2x80x9d, Sensors and Actuators B 51 (1998) 17-24, described a method of making optical sensors for several species that can be interrogated with one optical source and one detector. Although it would appear that an instrument based on this concept should be simple and inexpensive, the sensors themselves are highly non-selective. Wolfbeis et al. have shown that these sensors respond to pH. Therefore, such sensors would be unsuitable in an environment in which the pH changes. Moreover, prior literature, such as Mauze et al, xe2x80x9cNon-crosslinked Organosilicon matrix for Luminescent Quenching based Fiber Optic Oxygen Sensorsxe2x80x9d SPIE Proceedings, Vol. 1886, (1993), has shown that the luminophore of these sensors is also oxygen sensitive. These sensors, as described by Wolfbeis et al., are therefore not as such applicable for measurements in changing oxygen environment either.
Another type of prior sensing devices utilize arrays of sensors that are highly non-specific to the volatile analytes in the sample. Such devices are described in, for example, U.S. Pat. Nos. 5,698,089, 5,788,833, and in Ballantine et al., Anal Chem. 1986, 58, 3058-3066. Such arrays consist of sensors that measure physical, optical, or electrical properties, such as density, refractive index or electrical resistance, respectively, which change in relation to the concentrations of the species that penetrate to the sensing element of the sensors. The changes in such properties are measured and the data are analyzed using pattern recognition techniques to determine the concentration of each species. Such sensors have a limited dynamic range dictated by the properties of the sensing region. Moreover, these sensing arrays can be used only for analyzing volatile species. These sensors respond to any species that penetrates the sensing region. Calibration models or training sets have to be designed to include all such species that might be present in the sample. Thus they are prone to failure when an outliner species is encountered.
Designing a sensor that responds only to one analyte is a very difficult task. Many sensors that have been tried were abandoned because interferences by one or more other analytes could not be removed. Often it is just one species that interferes with the measurement. In such cases, attempts have been made to design a sensor specifically for the interfering species without interference from others and mathematically correct for the interference. But such an added sensor requires a new method of interrogating the sensor. This adds complexity to the instrument. The challenge is particularly daunting when a large number of analytes are to be measured and many species interfere with one another. Often it is not possible to make a highly specific sensor for an interfering species.
There is a need for a reliable method of analyzing multiple species in a sample using a simple instrument, for example, a single source-detector unit. Moreover, it is desirable to ensure that the devices do not respond in an intractable way to the other non-target known or unknown species that might be present in the sample. It is also desirable to make the device applicable to non-volatile species as well as to the volatile species in the sample. The present invention meets these needs and provides a technique for analyzing multiple analytes simultaneously (for example, the analytes in a sample of a liquid of unknown composition). The present technique uses a plurality of sensors to sense a plurality of analytes wherein some of the analytes may interfere with the sensors that sense other analytes and relates the responses of the sensors such that the analytes are sensed accurately in spite of the fact that the analytes may be interfering with one another.
In one aspect, the present invention provides an apparatus for analyzing multiple analytes in an unknown fluid (i.e., sample of an unknown liquid composition) simultaneously. The apparatus includes a plurality of sensors each for exposing to a sample of the unknown. The plurality of sensors includes groups of sensors wherein each group targets a specific analyte and includes one or more sensors including an analyte-specific chemical that interacts more specifically with one analyte than with other analytes to be analyzed. Each sensor in a group has a different chemical interacting specifically with the analyte. A light source is present in the apparatus for providing light to shine on the sensors to cause light interaction with the sensors. Differences in the sensors lead to differences in light interaction with the sensors. Detectors are used to determine the light interaction by the sensors. A processor is used for analyzing the light interaction by the sensors to take into account interference in light interaction among the analytes, thereby determining the concentration of each of the analytes in the unknown fluid. The present invention also provides a method of analyzing simultaneously multiple analytes in an unknown fluid and a method of making the apparatus for analysis.
In one aspect, the present technique involves converting the analysis of a large number of analytes to the analysis of a smaller number of chemicals such that the concentration of those smaller number of chemicals can be analyzed using a simple detection method. In an embodiment, certain ions are sensed via a chemistry that changes the pH in a sensor by the ions. In another embodiment, certain chemicals are sensed via a chemistry that changes the concentration of oxygen in the sensor.
Using the technique of the present invention, one can advantageously use a compact detecting instrument to conveniently sense the concentration or presence of a multitude of analytes simultaneously even though the analytes may interfere with one another. Because of the unique feature of using chemical conversion to render the sensing of many analytes into the sensing of a few common chemicals or ions (e.g., oxygen and hydrogen ion), the same chemistry or detection technique can be used to determine the concentration or presence of these few common chemicals and ions. As a result, a smaller number of light source for interrogating the sensors and a smaller number of types of detectors can be used for detection of changes in the sensors. Such factors will result in simpler and more compact apparatuses for analyzing analytes.
The present technique is particularly useful in medicine. An example of fluids that could be analyzed using the devices and methods of this invention is blood. Convenient measurement of blood analytes will greatly enhance the ease and convenience of monitoring the health status of patients. Multiple analytes to be measured in such an exemplary fluid can includes pH, PO2, PCO2, K+, Na+, Ca++, Mg++, glucose, lactate, creatinine, blood urea nitrogen (BUN), Hct, Hb, bilirubin, therapeutic drugs, drugs of abuse, etc. Although the example described below refers to an aqueous fluid, the invention is also applicable to analyzing other fluids such as gases or other liquids. The invention applies more particularly to a skin-pricking device that is capable of transporting fluid from the skin. Further, the present invention is applicable for analyzing fluids in nonmedical fields, such as environmental samples, samples in manufacturing processes, etc.